The overall goal of this project is to gain insight into cell trafficking and activation in multiple sclerosis (MS). We focus on chemokines and chemokine receptors, which are expressed both on infiltrating leukocytes and microglia in the central nervous system (CNS). Our general hypothesis is that chemokines and their receptors help determine the specific character of inflammatory CNS infiltrates. Recently, successful clinical trials of anti-leukointegrin antibodies validated the approach of blocking leukocyte trafficking to suppress inflammation in MS and phase II trials of small molecule chemokine receptor antagonists for treating MS are in progress. Therefore, it is increasingly important to delineate how chemokines and their receptors function during the evolution of MS, and clarify appropriate treatment targets. The Specific Aims of this competing renewal will focus on the following key issues: First, how do chemokines regulate initial entry of blood-borne leukocytes into the CSF and CNS parenchyma? Second, how do chemokines govern migration and activation of blood-derived leukocytes and microglia within the inflamed parenchyma ? Third, what is the role of chemokines and their receptors in the compartmentalized inflammatory reaction of progressive MS? Our proposed research will examine in detail the roles of chemokines and their receptors in the pathogenesis of MS in its varied forms and phases, and will identify targets for treatment with chemokine receptor antagonists.